Type 1 diabetes (T1D) is characterized by the T cell-mediated destruction of the pancreatic beta cells. The precise mechanisms that over-ride self-tolerance remain ill-defined; however, aberrant thymic selection is believed to contribute to the development of pathogenic beta cell-specific T cells. Recently, we found that the progression of beta cell autoimmunity is blocked in nonobese diabetic (NOD) mice deficient in the expression of MerTK (NOD.mertkkd). Preliminary findings suggest that the lack of diabetes in NOD.mertkkd mice is due to enhanced thymic negative selection of beta cell-specific thymocytes. MerTK is a receptor tyrosine kinase expressed by macrophages and dendritic cells (DC), and is involved in apoptotic cell engulfment and down-regulating activation and function of these innate effector cells. Furthermore, we recently showed that MerTK signaling in DC has a key role in mediating the inhibitory effects of apoptotic cells. The latter is believed to be a mechanism by which DC are regulated to maintain self-tolerance. Notably, the gene encoding MerTK is located in the NOD Idd13 susceptibility locus, and is conserved in the human IDDM12/13 interval. Our findings made in NOD.mertkkd mice suggest that Mertk is a candidate gene contributing to T1D. Accordingly, the current application has two goals. The first is to test the hypothesis that MerTK regulates homeostatic activation of thymic DC, and in turn the efficiency of thymocytes negative selection. The second goal is to determine whether MerTK contributes to the "spontaneous" progression of T1D. This work will provide novel insight into how thymic selection and the progression of beta cell autoimmunity are regulated by MerTK. [unreadable] [unreadable] [unreadable]